Scientists have for the first time seen how the body senses cold at the molecular level
For most people, the sensation of cold seems almost self-evident: it is enough to immerse a hand in ice, step out into winter air, or feel the refreshing trace of menthol from toothpaste for the nervous system to immediately send a clear message to the brain. Behind this seemingly simple sensation, however, lies a complex biological mechanism that for decades eluded precise explanation. Researchers from the University of California, San Francisco have now announced that they have for the first time managed to show, practically frame by frame, how the TRPM8 protein is activated, the main molecular sensor of cold in nerve cells. The paper was published on March 25, 2026, in the journal Nature and represents an important step forward in understanding the way the body registers a drop in temperature, as well as in the development of future therapies against certain forms of pain.
TRPM8 is an ion channel, that is, a protein structure in the membrane of a nerve cell that behaves like tiny gates. When the temperature drops below approximately 26 degrees Celsius, or when it is activated by compounds such as menthol, these gates open and trigger an electrical signal that travels to the brain. A person experiences that signal as cold. Scientists have long known that TRPM8 plays a key role in this process, but what was missing was a clear picture of how the protein actually changes as it moves from a closed to an open state. That transition was precisely one of the major open questions of modern sensory neurobiology.
Why this discovery matters
The new research offers not only an attractive molecular picture of a natural sensation, but also a concrete scientific foundation for understanding disorders in which even mild cooling causes intense pain. In such conditions, known as cold allodynia, the nervous system reacts excessively and painfully to cold. This can occur in neuropathic pain, after nerve damage, or as a side effect of certain forms of chemotherapy. The better the mechanism of TRPM8 channel opening is understood, the greater the possibility that drugs may be developed in the future that would more precisely dampen the pathological reaction to cold without impairing other important functions of the nervous system.
The authors of the paper point out that a particularly important moment was managing to track the protein in motion, and not only in one rigid, laboratory-stabilized form. That is also the reason why the answer took so long to arrive. Structural biology has for years been extremely successful at recording proteins in stable states, but it is much harder to capture the transitional forms that actually determine how a protein works. In the case of TRPM8, the problem was even more pronounced because that protein, when isolated from the natural membrane of the nerve cell, proved to be very sensitive and prone to breaking down.
How researchers managed to “capture” the cold protein
The teams of David Julius and Yifan Cheng bypassed that problem by not observing TRPM8 as an isolated laboratory sample, but while it was still located in membranes obtained from cells. In doing so, they preserved conditions that are closer to its natural environment. According to the researchers’ explanation, it was precisely this approach that made it possible for the first time to see the real changes in shape while the protein reacts to cold.
The scientists combined two complementary methods in the process. The first was cryogenic electron microscopy, known as cryo-EM, which enables extremely detailed three-dimensional displays of protein structures. Samples were prepared under different conditions, in the cold, with menthol, and at room temperature, and were then rapidly frozen in order to “lock” the state of the protein at a precisely defined moment. In this way, a series of very precise structural images at the atomic level was obtained.
The second method was hydrogen-deuterium exchange mass spectrometry, or HDX-MS. Unlike cryo-EM, which provides a kind of photograph, HDX-MS helps track which parts of the molecule are flexible, which move, and how the protein changes energetically as the temperature falls. By combining these two methods, the researchers were able not only to see the shape of TRPM8 but also to reconstruct the logic of its opening. This is an important advance for the field of sensory neurobiology because it shows that the function of a protein does not depend only on one final structure, but on an entire series of transitional states.
What happens when it gets cold
According to the results published in Nature, cold stabilizes a certain region of the TRPM8 channel. That stabilization then triggers the movement of one key helical structure, the so-called S6 helix, which participates in opening the passage through the channel. In that process, a lipid molecule also takes on an important role by entering a newly formed site and helping to “lock” the channel in the open state. In other words, the protein does not respond to cold only by passive bending, but through a series of coordinated structural and energetic changes that together maintain the cold signal long enough for the nervous system to register it.
The authors of the paper also describe a new, so-called semi-swapped channel architecture, in which the arrangement of certain parts between neighboring subunits changes significantly. This is an important detail because it shows that TRPM8 does not function as a simple switch with two positions, on and off, but as a dynamic system that passes through several intermediate steps. It is precisely such intermediate steps that are often crucial for drug development, because therapeutic molecules can be designed to act on a precisely defined state of the protein, and not necessarily on its fully open or fully closed form.
For the broader public, this means that the sensation of cold is not the result of a single “temperature button” in the body, but of a precisely tuned molecular machine. When the external temperature drops or when menthol chemically imitates the effect of cooling, TRPM8 enters a more energetically favorable state in which a pathway opens for ions. Those ions change the electrical properties of the nerve cell and create a signal that the brain recognizes as cold. What until recently could be described only indirectly, through physiological experiments and electrical measurements, has now for the first time received a clear three-dimensional structural basis.
Why birds feel cold differently from mammals
One of the more interesting conclusions of the paper concerns the comparison of the human TRPM8 protein with the avian version of the same channel. Birds also have TRPM8 in their nerve cells, and their protein can respond to menthol, but sensitivity to cold itself is significantly lower than in mammals. By comparing those two variants, the researchers were able to identify which structural features are crucial specifically for the detection of cold. That does not mean that all differences among species in tolerating cold environments have been exhaustively explained, but it opens an important window into the evolutionary adaptation of thermoreception.
Such knowledge has broader scientific value. Temperature sensitivity is not the same in all animals, and evolution has adapted the nervous system of different species to the environment in which they live. If it is now known which parts of TRPM8 contribute the most to cold sensitivity, it is possible to investigate more precisely how different species have adapted to colder or warmer habitats. At the same time, the question is opened as to whether similar mechanisms can also be found in other temperature-sensitive channels.
The role of David Julius and the broader context of sensory research
The paper is given special weight by the fact that it is co-authored by David Julius, the scientist who in 2021 received the Nobel Prize in Physiology or Medicine for discoveries of receptors for temperature and touch. The Nobel Prize was awarded to him together with Ardem Patapoutian, and Julius is best known for his work on the TRPV1 protein, the receptor that enables the sensation of the pungency of chili peppers and heat. His earlier discovery opened an entirely new chapter in understanding how nerve cells translate physical and chemical stimuli into sensation.
That is precisely why the new paper on TRPM8 also has symbolic value. After the protein that helps explain the sensation of heat and burning, the key protein of the sensation of cold has now also been explained much more clearly. This further reinforces the picture according to which basic bodily sensations, those that people take for granted every day, are based on very specific molecular gates in the membranes of nerve cells. When those gates open or close, what later we experience as cold, hot, painful, or pleasantly refreshing arises.
What this could mean for pain treatment
For now, this is not a drug or an immediate therapeutic application, but a fundamental scientific discovery. Still, it is precisely works like this that often create the foundation for the later development of targeted medicines. In the scientific literature, TRPM8 has already for some time been viewed as an important target for treating painful conditions associated with cold. If researchers now better understand which regions of the channel participate in its activation and stabilization of the open state, the pharmacological approach can become more precise. Instead of roughly blocking the entire system, it would theoretically be possible to develop compounds that act only on certain transitional phases of channel opening.
This is especially important because the nervous system is not a simple mechanism in which one function can be switched off without consequences. Cold is an important protective signal of the organism. The body must know how to distinguish pleasant coolness from potentially dangerous hypothermia. Because of that, future therapies would have to be precise enough to reduce pathological pain without removing the body’s normal ability to recognize dangerous cold. The new research does not solve that challenge, but for the first time places it on a much firmer molecular basis.
More than one protein photograph
Perhaps the most important message of the paper is broader than cold itself. The authors emphasize that the behavior of many proteins cannot be understood from a single “snapshot.” Just as a photograph of a horse does not show exactly how it runs, a single static image of a protein does not reveal the mechanics of its function. In that sense, this paper also represents a methodological lesson for structural biology. It shows that, to understand function, it is often necessary to combine extremely detailed structural techniques with methods that reveal the movement, flexibility, and energetics of the molecule.
This is important for other areas of biology and medicine as well. Many receptors, ion channels, and enzymes work precisely by transitioning between several short-lived states. If they are observed only in one stable position, a key part of the story remains hidden. TRPM8 has therefore, besides being a sensor of cold, also become an example of how proteins can be studied that for a long time were too “restless” or too sensitive to be shown at the moment of real function.
Researchers at UCSF have already announced that they want to apply the same strategy to TRPV1 as well, the heat-sensitive channel that Julius described back in 1997. This means that in the coming years even more detailed depictions of the molecular mechanisms by which the human body distinguishes warm from cold, pleasant from painful, and protective from harmful may follow. For the public, perhaps the most appealing part of the story is the fact that this resolves a long-standing scientific mystery. For medicine, it is even more important that each new insight into these mechanisms brings closer the possibility of more precise pain treatment, especially where cold grows from a normal sensation into a serious and exhausting problem.
Sources:- UC San Francisco – official announcement about the research, cryo-EM and HDX-MS methods, and possible consequences for understanding pain (link)
- Nature – the original scientific paper “Structural energetics of cold sensitivity,” published on March 25, 2026, with a description of the activation mechanism of the TRPM8 channel (link)
- Nobel Prize – David Julius’s official profile and the explanation of the 2021 Nobel Prize in Physiology or Medicine for discoveries of receptors for temperature and touch (link)
- Scientific American – a journalistic overview of the significance of the discovery and possible implications for understanding hypersensitivity to cold in patients (link)
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